10-68122195-G-C
Variant summary
Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_ModerateBS1_SupportingBS2
The NM_032578.4(MYPN):c.757G>C(p.Gly253Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00011 in 1,609,532 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Consequence
NM_032578.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Benign. Variant got -7 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | Exon rank | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
MYPN | NM_032578.4 | c.757G>C | p.Gly253Arg | missense_variant | Exon 2 of 20 | ENST00000358913.10 | NP_115967.2 |
Ensembl
Frequencies
GnomAD3 genomes AF: 0.0000788 AC: 12AN: 152204Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000688 AC: 17AN: 247048Hom.: 0 AF XY: 0.0000674 AC XY: 9AN XY: 133450
GnomAD4 exome AF: 0.000113 AC: 165AN: 1457210Hom.: 0 Cov.: 31 AF XY: 0.000105 AC XY: 76AN XY: 724516
GnomAD4 genome AF: 0.0000788 AC: 12AN: 152322Hom.: 0 Cov.: 32 AF XY: 0.0000940 AC XY: 7AN XY: 74478
ClinVar
Submissions by phenotype
not provided Uncertain:2
The MYPN c.757G>C; p.Gly253Arg variant (rs201983087), to our knowledge, is not reported in the medical literature but is reported in ClinVar (Variation ID: 222748). This variant is found in the non-Finnish European population with an allele frequency of 0.011% (14/127,482 alleles) in the Genome Aggregation Database. The glycine at codon 253 is weakly conserved, and computational analyses predict that this variant is neutral (REVEL: 0.11). Due to limited information, the clinical significance of the p.Gly253Arg variant is uncertain at this time. -
Has not been previously published as pathogenic or benign to our knowledge; In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function -
Dilated cardiomyopathy 1KK;C4479186:MYPN-related myopathy Uncertain:2
The p.Gly253Arg variant in the MYPN gene has not been previously reported in association with disease. This variant has been identified in 14/127482 European (non-Finnish) chromosomes (18/278450 chromosomes overall) by the Genome Aggregation Database (http://gnomad.broadinstitute.org/) Although this variant has been seen in the general population, its frequency is low enough to be consistent with the prevalence of cardiomyopathy. This variant is present in ClinVar (Variation ID: 222748). Computational tools predict that this variant does not impact protein function; however, the accuracy of in silico algorithms is limited. These data were assessed using the ACMG/AMP variant interpretation guidelines. In summary, the significance of the p.Gly253Arg variant is uncertain. Additional information is needed to resolve the significance of this variant. [ACMG evidence codes used: BP4] -
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Left ventricular noncompaction cardiomyopathy Uncertain:1
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Dilated cardiomyopathy 1KK Uncertain:1
This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 253 of the MYPN protein (p.Gly253Arg). This variant is present in population databases (rs201983087, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with MYPN-related conditions. ClinVar contains an entry for this variant (Variation ID: 222748). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Cardiovascular phenotype Uncertain:1
The p.G253R variant (also known as c.757G>C), located in coding exon 1 of the MYPN gene, results from a G to C substitution at nucleotide position 757. The glycine at codon 253 is replaced by arginine, an amino acid with dissimilar properties. This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at